Progressive endothelin-1 gene activation initiates chronic/end-stage renal disease following experimental ischemic/reperfusion injury.
Progressive endothelin-1 gene activation initiates chronic/end-stage renal disease following experimental ischemic/reperfusion injury.
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DOI：
10.1038/ki.2013.157
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发表时间：
2013-10
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
--
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这项研究评估了内皮素-1（ET 1）是否有助于介导缺血后急性肾损伤（阿基）进展为慢性肾脏疾病（CKD）。在CD-1小鼠单侧缺血30分钟后24小时或2周，评估有效ETA或ETB受体特异性拮抗剂（分别为阿曲生坦和BQ-788）对疾病进展的影响。单侧缺血引起进行性肾ET-1蛋白/mRNA增加，伴随ETA，但不是ETB，mRNA升高。广泛的组蛋白重塑与基因激活和RNA聚合酶II结合增加一致，发生在ET-1基因。单侧缺血产生进行性肾损伤，表现为严重的组织学损伤和40%的肾质量损失。缺血前和缺血后或仅缺血后用阿曲生坦治疗赋予显著的保护作用，例如减少小管/微血管损伤、使组织乳酸正常化和完全保留肾质量。阿曲生坦未增加细胞核KI-67染色，这意味着不涉及小管增殖增加。相反，ETB阻断没有保护作用。因此，我们的研究结果提供了第一个证据，即ET-1通过ETA发挥作用，可以在缺血性阿基进展为CKD中发挥关键作用。阻断ETA提供了戏剧性的保护，表明这些结果的功能意义。
This study assessed whether endothelin-1 (ET1) helps mediate post-ischemic acute kidney injury (AKI) progression to chronic kidney disease (CKD). The impact(s) of potent ETA or ETB receptor-specific antagonists (Atrasentan and BQ-788, respectively) on disease progression were assessed 24 hours or 2 weeks following 30 minutes of unilateral ischemia in CD-1 mice. Unilateral ischemia caused progressive renal ET-1 protein/mRNA increases with concomitant ETA, but not ETB, mRNA elevations. Extensive histone remodeling consistent with gene activation and increased RNA polymerase II binding occurred at the ET-1 gene. Unilateral ischemia produced progressive renal injury as indicated by severe histologic injury and a 40% loss of renal mass. Pre- and post-ischemia or just post-ischemic treatment with Atrasentan conferred dramatic protective effects such as decreased tubule/microvascular injury, normalized tissue lactate, and total preservation of renal mass. Nuclear KI-67 staining was not increased by Atrasentan, implying that increased tubule proliferation was not involved. Conversely, ETB blockade had no protective effect. Thus, our findings provide the first evidence that ET-1 operating through ETA can play a critical role in ischemic AKI progression to CKD. Blockade of ETA provided dramatic protection, indicating the functional significance of these results.
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